title: A novel hydroxysuberamide derivative potentiates MG132-mediated anticancer activity against human hormone refractory prostate cancers--the role of histone deacetylase and endoplasmic reticulum stress.
abstract: BACKGROUND
  Histone deacetylase (HDAC) inhibitors are successful for treatment of advanced cutaneous T-cell lymphoma but only show modest effect in solid tumors. Approaches for HDAC inhibitors to improve activity against solid tumors are necessary.
  
  
  METHODS
  Sulforhodamine B assay and flow cytometric analysis detected cell proliferation and cell-cycle progression, respectively. Protein expression was determined by Western blotting. Comet assay and DNA end-binding activity of Ku proteins detected DNA damage and DNA repair activity, respectively. siRNA technique was used for knockdown of specific cellular target.
  
  
  RESULTS
  WJ25591 displayed inhibitory activity against HDAC1 and cell proliferation in human hormone-refractory prostate cancers PC-3 and DU-145. WJ25591 caused an arrest of cell-cycle at both G1- and G2-phase and increased protein expressions of p21 and cyclin E, followed by cell apoptosis. WJ25591-induced Bcl-2 down-regulation and activation of caspase-9, -8, and -3, suggesting apoptotic execution through both intrinsic and extrinsic apoptotic pathways. WJ25591 also significantly inhibited DNA repair activity but not directly induced DNA damage. Moreover, the proteasome inhibitor MG-132 dramatically sensitized WJ25591-induced cell apoptosis. The siRNA technique demonstrated that endoplasmic reticulum (ER) stress, in particular CHOP/GADD153 up-regulation, contributed to the synergistic effect.
  
  
  CONCLUSIONS
  The data suggest that WJ25591 inhibited HDAC activity, leading to cell-cycle arrest and inhibition of DNA repair. Caspase cascades are subsequently triggered to execute cell apoptosis. MG-132 dramatically sensitizes WJ25591-mediated apoptosis, at least partly, through ER stress response. The data also reveal that combination of HDAC inhibitors and proteasome inhibitors may be a potential strategy against hormone-refractory prostate cancers.
authors.affiliation: College of Medicine, School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.forename: Jui-Ling
authors.initials: JL
authors.lastname: Hsu
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Yu
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Wang
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D061988:Proteasome Inhibitors / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D006655:Histone Deacetylases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: DNA repair; GADD153; HDAC inhibitor; intrinsic and extrinsic apoptosis pathways; proteasome inhibitor